Dnajb1-KO Mouse

Dnajb1, also known as DnaJ homolog subfamily B member 1, is involved in multiple cellular processes. It negatively regulates MIG6 to promote epidermal growth factor receptor signaling by enhancing K48-linked ubiquitination of MIG6 [6]. It also destabilizes PDCD5 through ubiquitin-mediated degradation, suppressing p53-mediated apoptosis [7].

The DNAJB1-PRKACA fusion is a significant finding related to Dnajb1. This fusion is the oncogenic driver in fibrolamellar hepatocellular carcinoma (FLC). Peptide-based immunotherapy targeting DNAJB1-PRKACA can induce multifunctional cytotoxic CD8+ and T-helper 1 CD4+ T cells, and vaccination with its-derived peptides can lead to durable relapse-free survival in FLC patients [1]. Endogenous CD8 T cell responses to this fusion in FLC patients are rare, but functional fusion-specific T cell receptors (TCRs) have been defined, which could be used in cellular immunotherapies [2]. The DNAJB1-PRKACA fusion drives FLC through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming [3]. It also regulates LINC00473, which promotes tumor growth and alters mitochondrial fitness in FLC [4,5]. Additionally, DNAJB1-PRKACA fusions are not specific to FLC as they also occur in oncocytic pancreatic and biliary neoplasms, and protein kinase inhibition could be a potential therapy for these neoplasms [8].

In conclusion, Dnajb1 plays important roles in regulating key cellular signaling pathways and apoptosis. The discovery of the DNAJB1-PRKACA fusion has illuminated its significance in FLC and other related neoplasms. Studies on this fusion, especially in the context of FLC, have provided insights into potential immunotherapeutic and targeted treatment strategies for these diseases.

References:

1. Bauer, Jens, Köhler, Natalie, Maringer, Yacine, Hailfinger, Stephan, Walz, Juliane S. 2022. The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma. In Nature communications, 13, 6401. doi:10.1038/s41467-022-33746-3. https://pubmed.ncbi.nlm.nih.gov/36302754/

2. Kirk, Allison M, Crawford, Jeremy Chase, Chou, Ching-Heng, Strome, Scott E, Thomas, Paul G. . DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma. In Cell reports. Medicine, 5, 101469. doi:10.1016/j.xcrm.2024.101469. https://pubmed.ncbi.nlm.nih.gov/38508137/

3. Gritti, Ilaria, Wan, Jinkai, Weeresekara, Vajira, Gujral, Taranjit S, Bardeesy, Nabeel. . DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming. In Cancer discovery, 15, 382-400. doi:10.1158/2159-8290.CD-24-0634. https://pubmed.ncbi.nlm.nih.gov/39326063/

4. Ma, Rosanna K, Tsai, Pei-Yin, Farghli, Alaa R, Barrow, Joeva, Sethupathy, Praveen. 2024. DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma. In PLoS genetics, 20, e1011216. doi:10.1371/journal.pgen.1011216. https://pubmed.ncbi.nlm.nih.gov/38512964/

5. Kim, Stephanie S, Kycia, Ina, Karski, Michael, Sethupathy, Praveen, Vakili, Khashayar. 2022. DNAJB1-PRKACA in HEK293T cells induces LINC00473 overexpression that depends on PKA signaling. In PloS one, 17, e0263829. doi:10.1371/journal.pone.0263829. https://pubmed.ncbi.nlm.nih.gov/35167623/

6. Park, Soo-Yeon, Choi, Hyo-Kyoung, Seo, Jae Sung, Choi, Kyung-Chul, Yoon, Ho-Geun. 2015. DNAJB1 negatively regulates MIG6 to promote epidermal growth factor receptor signaling. In Biochimica et biophysica acta, 1853, 2722-30. doi:10.1016/j.bbamcr.2015.07.024. https://pubmed.ncbi.nlm.nih.gov/26239118/

7. Cui, Xiandan, Choi, Hyo-Kyoung, Choi, Young-Seok, Choi, Kyung-Chul, Yoon, Ho-Geun. 2014. DNAJB1 destabilizes PDCD5 to suppress p53-mediated apoptosis. In Cancer letters, 357, 307-315. doi:10.1016/j.canlet.2014.11.041. https://pubmed.ncbi.nlm.nih.gov/25444898/

8. Vyas, Monika, Hechtman, Jaclyn F, Zhang, Yanming, Klimstra, David S, Basturk, Olca. 2019. DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma. In Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 33, 648-656. doi:10.1038/s41379-019-0398-2. https://pubmed.ncbi.nlm.nih.gov/31676785/